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Abstract

Recent studies have suggested that variations in adiponutrin, a novel gene involved in adipose tissue triglyceride cycling, are associated with insulin sensitivity and obesity. We performed microarray analysis on isolated liver parenchymal cells from LDL receptor deficient (LDLr−/−) mice that were fed a Western-type diet (0.25% cholesterol, 15% fat) for 0 to 6 weeks. Gene expression profiling revealed that adiponutrin was the most highly regulated gene with a marked ~50-fold induction upon Western-type diet feeding. Real-time quantitative PCR verification of the microarray data showed a 20-fold (P<0.001) increase in adiponutrin expression in total liver of LDLr−/− mice after 2 weeks of Western-type diet feeding. Interestingly, hepatic adiponutrin expression was also stimulated (2.1-fold; P<0.001) by fasting (~18h). In comparison, in another triglyceride cycling dependent tissue, (cardiac) muscle, Western-type diet feeding did not alter adiponutrin expression, whilst fasting stimulated adiponutrin expression 1.7-fold (P=0.032). In adipose tissue, fasting induced a striking 90% (P<0.001) decrease in adiponutrin expression, whereas Western-type diet did not significantly affect adiponutrin expression in adipose tissue. Based on these combined findings we propose that adiponutrin has a dual role in triglyceride cycling in the liver: during fasting adiponutrin is involved in triglyceride hydrolysis, whilst under high energy conditions it may play a role in triglyceride synthesis and lipogenesis. Additional analysis of the microarray data showed that parenchymal liver cell expression of the putative adiponutrin activator sterol regulatory element binding protein 1 (SREBP-1) was 1.7-fold increased, while analysis of a panel of microRNAs showed a 5.6-fold decrease in the putative inhibitor miRNA-216 upon Western-type diet feeding. In conclusion, we provide evidence that the obesity-linked gene adiponutrin is highly induced in liver parenchymal cells of LDLr−/− mice by a Western-type diet. Furthermore, we suggest that hepatic adiponutrin expression is regulated by the transcriptional regulators SREBP-1 and miR-216.